This proposal is designed to support the career development of Susan Fink, MD, PhD, a laboratory medicine physician (clinical pathologist) trained in cellular biology who has begun postdoctoral research under the guidance of Dr. Akiko Iwasaki. The proposed mentored research experience and career development activities describe a 5-year training program to give Dr. Fink the skills to become an independent investigator at an academic medical center, studying innate immune responses to viral infections. She will achieve this goal through the guidance of her mentors and advisory committee, coursework and seminars and development of scientific expertise in virology and immunology. Her mentor, Dr. Iwasaki is an established leader in immunology with a history of training successful young scientists, and the Departments of Immunobiology and Laboratory Medicine at Yale provide a rich scientific environment. Programmed cell death is a defense mechanism used by multicellular organisms to eliminate potentially harmful cells, including pathogen-infected cells. Dr. Fink's graduate research allowed her to identify pyroptosis, a novel form of pro-inflammatory programmed cell death triggered during bacterial infection. She seeks to build on her prior training to study cellular responses to infection in a setting in which she has less experience, namely viral infection. Dr. Fink's initial postdoctoral research has revealed the importance of apoptotic host cell death in response to two viruses: herpes simplex virus-1 and vesicular stomatitis virus. Her findings uncovered a pathway whereby activation of the host protein Ire1? inhibits apoptosis. Ire1? is activated during the unfolded protein response, a cellular pathway to detect and alleviate dysfunctional protein folding in the endoplasmic reticulum. Ire1? is also activated by genetic deficiency of it downstream target, Xbp1. Dr. Fink found that activation of Ire1? in Xbp1 genetically deficient cells caused resistance to apoptosis during infection with herpes simplex virus-1 and vesicular stomatitis virus. The inability of these infected cells to undergo apoptosis prolonged viral replication and significantly increased production of virus. These findings suggest the hypothesis that infections and cellular stresses that activate Ire1?? will also cause resistance to apoptosis. The experiments outlined in this proposal will determine the molecular mechanisms of Ire1?-mediated apoptosis resistance (Aim 1A) and examine whether viruses that trigger ER stress utilize this pathway (Aim 1B). In addition, this proposal will address the hypothesis that inhibition of basal Ire1? activity increases susceptibility to apoptosis (Aim 2A) and examine whether apoptosis susceptibility can be modulated as an antiviral therapeutic strategy (Aim 2B). Together these aims will illuminate inhibition of Ire1? as a novel therapeutic strategy to enhance the host response to diverse viral infections.